Establishing Neuronal Diversity: Regulation of olfactory receptor neuron specification and axon guidance in Drosophila
The human brain contains over 80 billion neurons that make approximately 100 trillion specific connections. Each neuron must acquire a specific identity that includes its, gene expression, morphology, connectivity, and location. The basic logic and mechanisms that are used to coordinate this process on the immense scale of the brain remain largely unknown. We use the Drosophila olfactory system as model to understand nervous system development because of the powerful genetic tools and the workable level of neuronal diversity, which contains 50 classes of olfactory receptor neurons (ORNs). Each class of neurons is defined by the exclusive expression of typically a single olfactory receptor and connect to 50 class-specific glomeruli in the antennal lobe of the brain. Here we demonstrate that a cross regulatory network of transcription factors patterns the antennal disc, which contains ORN precursors and will develop into the antenna. These transcription factors create seven rings that are each labeled by a unique combination of genes, which generate distinct sets of ORN fates. Manipulation of this network changes the ORN fates that are produced in the adult, thereby demonstrating its necessity for generating neuronal diversity. We next show that the DIP/Dpr family of proteins, which are members of the Ig superfamily of genes and heterophilically interact, is required for axon sorting among classes of ORNs to create 50 class specific glomeruli. The members of this family are expressed in a combinatorial code in ORNs at times that correlate to glomerular formation. Computational analysis of DIP/Dpr expression patterns groups ORN classes into clusters that mimics their relative glomerular positioning in the antennal lobe. Class-specific or combinatorial knock down of DIP and dpr genes causes localized axon sorting defects where effected class invade neighboring glomeruli based upon the similarity of the DIP/Dpr expression codes. Our results highlight two functionally conserved strategies for generating and wiring a diverse neural circuit: prepatterning of precursors through combinatorial transcription factor expression, and the generation of differential adhesion force between classes of axons through combinatorial interactions of cell surface molecules. Not only are these strategies conserved in mammals, many of the genes that govern these processes are conserved as well, with genes like Bar, ap, and dac all having mammalian orthologues, and DIPs and Dprs sharing homology with Kirrel proteins. These studies have advanced our knowledge of the underlying logic that governs how a diverse nervous system is generated and coordinately wired.
Olfactory system development
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